Accepted

Neuropathic pain after spinal cord injury (SCI) is a complex condition that responds poorly to usual treatments. Cell transplantation represents a promising therapy; nevertheless, the ideal cell type in terms of neurogenic potential and effectiveness against pain remains largely controversial. Here, we evaluated the ability of fetal neural stem cells (fNSC) to relieve chronic pain and, secondarily, their effects on motor recovery. Adult Wistar rats with traumatic SCI were treated, 10 days after injury, with intra-spinal injections of culture medium (sham) or fNSCs extracted from telencephalic vesicles (TV group) or the ventral medulla (VM group) of E/14 embryos. Sensory (von Frey filaments and hot plate) and motor (the Basso, Beattie, Bresnahan locomotor rating scale and inclined plane test) assessments were performed during 8 weeks. Thereafter, spinal cords were processed for immunofluorescence and transplanted cells were quantified by stereology. The results showed improvement of thermal hyperalgesia in the TV and VM groups at 4 and 5 weeks after transplantation, respectively. Moreover, mechanical allodynia improved in both the TV and VM groups at 8 weeks. No significant motor recovery was observed in the TV or VM groups compared with sham. Stereological analyses showed that ~70% of TV and VM cells differentiated into NeuN neurons, with a high proportion of enkephalinergic and GABAergic cells in the TV group and enkephalinergic and serotoninergic cells in the VM group. Our study suggests that neuronal precursors from TV and VM, once implanted into the injured spinal cord, maturate into different neuronal subtypes, mainly GABAergic, serotoninergic, and enkephalinergic, and all subtypes alleviate pain, despite no significant motor recovery. The study was approved by the Animal Ethics Committee of the Medical School of the University of São Paulo (protocol number 033/14) on March 4, 2016.

We report the development and characterization of a novel, injury-free rat model in which nociceptive sensitization following red light is observed in multiple body areas reminiscent of widespread pain in functional pain syndromes. Rats were exposed to red light emitting diodes (RLED) (LEDs, 660 nanometer) at an intensity of 50 Lux for 8 hours daily for 5 days resulting in time- and dose-dependent thermal hyperalgesia and mechanical allodynia in both male and female rats. Females showed earlier onset of mechanical allodynia than males. The pronociceptive effects of RLED were mediated through the visual system. RLED-induced thermal hyperalgesia and mechanical allodynia were reversed with medications commonly used for widespread pain including gabapentin, tricyclic antidepressants, serotonin/norepinephrine reuptake inhibitors, and NSAIDs. Acetaminophen failed to reverse the RLED induced hypersensitivity. The hyperalgesic effects of RLED were blocked when bicuculline, a GABA-A receptor antagonist, was administered into the rostral ventromedial medulla (RVM) suggesting a role for increased descending facilitation in the pain pathway. Key experiments were subjected to a replication study with randomization, investigator-blinding, inclusion of all data and high levels of statistical rigor. RLED induced thermal hyperalgesia and mechanical allodynia without injury offers a novel injury free rodent model useful for the study of functional pain syndromes with widespread pain. RLED exposure also emphasizes the different biological effects of different colors light exposure. Perspective: This study demonstrates the effect of light exposure on nociceptive thresholds. These biological effects of red LED adds evidence to the emerging understanding of biological effects of light of different colors in animals and humans. Understanding the underlying biology of red light-induced wide spread pain may offer insights into functional pain states.